Stability Program Management

With regulatory authorities having an increased focus on safety and efficacy, a new drug product often requires at least 10 years of development time before reaching its intended market. An important element of this lifecycle is the determination of shelf-life (i.e., stability) of the drug product under various anticipated storage conditions. The stability studies examine the safety and efficacy of the drug product as a function of its exposure to certain defined environmental factors over time. For a contract research organization (CRO) that operates under GMP and whose sponsors have products that are globally marketed, it is important to understand the guidelines and regulations that govern the global pharmaceutical industry.

When global distribution is the intent, it is crucial to assess product stability for the climate zones that the product will be subjected to during its manufacture, distribution, and usage. Although the pharmaceutical industry has recommended climate zones for long-term stability testing, a country can require condition(s) outside of this scope for its long-term storage (see Table I)(1).

For example, Europe, Japan, and the US adhere to their own practices, and have also adopted the International Conference on Harmonization (ICH) guidelines. Specifically, they follow Q1A (R2) Stability Testing of New Drug Substances and Products, which defines the stability data package for a new drug substance or drug product that is sufficient for a registration application (2). Other countries or regions do not necessarily follow these guidelines. For example, Brazil, India, and China, to name a few, have their own regulatory guidelines for stability. In addition to countries, agencies such as the World Health Organization (WHO) have their own stability guidelines. For Climate Zones III and IV, the ICH withdrew its Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV guideline in 2006. ICH left the definitions of storage conditions in Climatic Zones III and IV to the appropriate countries, regions, and the WHO. Also, if the medication is to be used for veterinary purposes, it may or may not be subject to any of the above regulatory agencies on top of the Center for Veterinary Medicine (CVM), the US Department of Agriculture (USDA), or the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH).

Given the current regulatory environment, sponsors may require CROs to provide substantially more resources in support of a stability program than in years past. Consider the following: to support a general case drug product several years ago, evaluating product stability at 25 °C ± 2 °C/60% RH ± 5% RH (where RH is relative humidity) for 12 months (or longer) was considered sufficient. Now, however, a stability study may also need to be performed at 30 °C ± 2 °C/65% RH ± 5% RH or a combination of both the 25 °C ± 2 °C/60% RH ± 5% RH and 30 °C ± 2 °C/65% RH ± 5% RH. There are also cases where the long-term storage of a general case drug product will need to be at 30 °C ± 2 °C/75% RH ± 5% RH. Besides long-term storage conditions for general case drug products, testing using intermediate (30 °C ± 2 °C/65% RH ± 5% RH) and accelerated (40 °C ± 2 °C/75% RH ± 5% RH) storage conditions is also required for a minimum of six months. Note: if the long-term stability storage of 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH has been performed, no intermediate condition is necessary (1, 2).